Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

Characteristic alkaloids from Stemona sessilifolia with lung protective effects.

In the research on lung protective effects from the roots of Stemona sessilifolia, twenty-five Stemona alkaloids have been isolated, including four undescribed components (1, 3-5), a new natural product (2) and 20 known alkaloids (6-25). Their structures were analyzed by NMR spectra, high-resolution mass spectrum data, and other chemical methods. UPLC-QTOF/MS method was used to identify the Stemona alkaloids and summarize the fragmentation patterns of mass spectrometry. The lung-protective effects of these compounds were evaluated using MLE-12 cells induced by NNK and nm SiO2. The results showed that compounds 3, 5, 8, 10-11, 17-21 and 23 exhibited protective effects on NNK-induced cell injury. Compounds 2, 8-11, 14, 17-19 and 22 showed improvement in nm SiO2-induced lung epithelial cell injury. Compound 10 (tuberostemonine D), a representative alkaloid with a high content in Stemona sessilifolia, significantly protected C57BL/6 lung injury mice induced by nm SiO2, suggesting it a key component of Stemona alkaloids that play a protective role in lung injury. The results of in vivo activity showed that compound 10 could improve the lung injury of mice, reduce ROS content, and recover the levels of SOD and MDA in serum. Its protective effect on lung injury might be related to Nrf2 activation.

Human Papillomavirus Infection in Penile Cancer: Multidimensional Mechanisms and Vaccine Strategies.

Penile cancer (PC) is a rare male malignant tumor, with early lymph node metastasis and poor prognosis. Human papillomavirus (HPV) plays a key role in the carcinogenesis of PC. This review aims to summarize the association between HPV infection and PC in terms of virus-host genome integration patterns (the disrupted regions in the HPV and PC genome), genetic alterations, and epigenetic regulation (methylation and microRNA modification) occurring in HPV and PC DNA, as well as tumor immune microenvironment reprogramming. In addition, the potential of HPV vaccination strategies for PC prevention and treatment is discussed. Understanding of the HPV-related multidimensional mechanisms and the application of HPV vaccines will promote rational and novel management of PC.

Development and validation of a novel clinical prediction model to predict the 90-day functional outcome of spontaneous intracerebral hemorrhage.

Background: Spontaneous intracerebral hemorrhage (SICH) is associated with high mortality and disability. Accurately predicting adverse prognostic risks of SICH is helpful in developing risk stratification and precision medicine strategies for this phenomenon. Methods: We analyzed 413 patients with SICH admitted to Hefei Second People's Hospital as a training cohort, considering 74 patients from the First Affiliated Hospital of Anhui Medical University for external validation. Univariate and multivariate logistic regression analyses were used to select risk factors for 90-day functional outcomes, and a nomogram was developed to predict their incidence in patients. Discrimination, fitting performance, and clinical utility of the resulting nomogram were evaluated through receiver operating characteristic (ROC) curves, accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), calibration plots, and decision curves analysis (DCA), respectively. Results: Of the 413 patients, 180 had a poor prognosis. Univariate analysis showed significant variance of age, systolic pressure, intraventricular hemorrhage (IVH), Glasgow Coma Scale (GCS) scores, National Institute of Health Stroke Scale (NIHSS) scores, and hematoma volume between the groups (p < 0.05). Logistic multivariate regression analysis showed that age, IVH, NIHSS, and hematoma volume were associated with unfavorable outcomes. Based on the results, a nomogram model was developed with an area under the ROC curve of 0.91 (95% CI; 0.88-0.94) and 0.89 (95% CI; 0.80-0.95) in the training and validation sets, respectively. In the validation set, the accuracy, sensitivity, specificity, PPV, and NPV of the model were 0.851, 0.923, 0.812, 0.727, and 0.951, respectively. The calibration plot demonstrates the goodness of fit between the nomogram predictions and actual observations. Finally, DCA indicated significant clinical adaptability. Conclusion: We developed and validated a short-term prognostic nomogram model for patients with SICH including NIHSS scores, age, hematoma volume, and IVH. This model has valuable potential in predicting the prognosis of patients with SICH.

Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) with a poor prognosis lacks reliable biomarkers for stratifying patients. Fas-associated death domain (FADD) could regulate cell proliferation and has shown promising diagnostic and prognostic significance in multiple cancers. However, researchers have not determined how FADD exerts its effect on PSCC. In this study, we set out to investigate the clinical features of FADD and the prognostic impact of PSCC. Additionally, we also assessed the role of affecting the immune environment in PSCC. Immunohistochemistry was carried out to evaluate the protein expression of FADD. The difference between FADDhigh and FADDlow was explored by RNA sequencing from available cases. The immune environment evaluation of CD4, CD8, and Foxp3 was performed by immunohistochemical. In this study, we found that FADD was overexpressed in 19.6 (39/199) patients, and the overexpression of FADD was associated with phimosis (p=0.007), N stage (p<0.001), clinical stage (p=0.001), and histologic grade (p=0.005). The overexpression of FADD was an independent prognostic factor for both PFS (HR 3.976, 95% CI 2.413-6.553, p<0.001) and OS (HR 4.134, 95% CI 2.358-7.247, p<0.001). In addition, overexpression of FADD was mainly linked to T cell activation and PD-L1 expression combined with PD-L1 checkpoint in cancer. Further validation demonstrated that overexpression of FADD was positively correlated with the infiltration of Foxp3 in PSCC (p=0.0142). It is the first time to show that overexpression of FADD is an adjunct biomarker with poor prognosis in PSCC and could also serve as a tumor immune environment regulator.

Negative impacts of nanoplastics on the purification function of submerged plants in constructed wetlands: Responses of oxidative stress and metabolic processes.

Constructed wetlands (CWs) are an important barrier to prevent nanoplastics (NPs) and microplastics (MPs) from entering receiving streams. However, little is known about how the accumulation of NPs affects the growth, photosynthesis, oxidative stress responses, and metabolism of plants, especially submerged plants that are widely used in CWs for water purification. Herein, we adopted Utricularia vulgaris (U. vulgaris), a typical submerged macrophyte as the model plant to address the above knowledge gaps under exposure to polystyrene NPs (PS-NPs, 500 nm, 0∼10 mg·L-1). Results showed that PS-NPs were absorbed by insect traps and further transported to stems and leaves of U. vulgaris, which limited plant height (6.8∼72.9%), relative growth rate (7.4∼17.2%), and photosynthesis (3.7∼28.2%). U. vulgaris suffered from oxidative stresses, as evidenced by the increase in malondialdehyde, antioxidant enzymes (catalase, peroxidase, and superoxide dismutase), and H2O2, especially under 1 and 10 mg·L-1. Abundances of 548 metabolites were quantified, and 291 metabolites were detected with altered levels after exposure, in which 25∼34% metabolites were up-regulated, and 32∼40% metabolites were down-regulated in metabolite expression. Metabolic pathways of the tricarboxylic acid cycle and amino acid were disrupted, in which citric acid, threonine, and adenine decreased, while amino acids (like serine, phenylalanine, histidine, etc.) increased first and then decreased with increasing PS-NPs concentrations. Moreover, PS-NPs reduced the removal efficiency of total nitrogen and phosphorus from water by U. vulgaris, bringing potential risks to aquatic ecosystems. These findings have greatly enhanced our understanding of the metabolic mechanisms and interactions of aquatic macrophytes that are heavily used in CWs in response to NPs stress, as well as the impact of NPs on CWs functioning.

Nomogram for predicting traumatic subdural effusion after mild traumatic brain injury.

Objective: Traumatic subdural effusion (TSE) is a common complication of traumatic brain injury (TBI). This study aimed to determine the risk factors associated with subdural effusion and to propose a nomogram to predict the risk of TSE in patients with mild TBI. Methods: We retrospectively analyzed 120 patients with mild TBI between January 2015 and December 2020 at the Third People's Hospital of Hefei. The risk factors of TSE were selected using univariate and multivariable logistic regression analysis. A nomogram was developed to predict the incidence of TSE. Receiver operating characteristics and calibration plots were used to evaluate the discrimination and fitting performance. Results: Of the 120 patients, 32 developed subdural effusion after mild TBI. Univariate analysis showed that gender, age, history of hypertension, traumatic subarachnoid hemorrhage, subdural hematoma, basilar skull fracture, and cerebral contusion were varied significantly between groups (p < 0.05). Logistic multivariate regression analysis showed that the gender, age, history of hypertension, and basilar skull fracture were independent risk factors for TSE. Based on these results, a nomogram model was developed. The C-index of the nomogram was 0.78 (95% CI: 0.70-0.87). The nomogram had an area under the receiver operating characteristic curve of 0.78 (95% CI: 0.70-0.87). The calibration plot demonstrated the goodness of fit between the nomogram predictions and actual observations. Conclusion: Gender, age, history of hypertension, and basilar skull fracture can be used in a nomogram to predict subdural effusion after mild TBI.

Effectiveness and safety of combined therapy versus monotherapy based on immune checkpoint inhibitors and/or targeted drugs as salvage treatment for advanced urothelial carcinoma: a systematic review and meta-analysis.

BACKGROUND: The standard salvage regimen for the patients with advanced urothelial carcinoma (UC) is uncertain, although lots of novel agents are recommended, including immune checkpoint inhibitors (ICIs) and targeted drugs (TDs). We aimed to compare the effectiveness and safety of combined therapy of novel agents (CNA) and monotherapy of novel agents (MNA) as salvage therapy for advanced UC. METHODS: Studies exploring CNA and/or MNA for advanced UC in second-line setting were searched from PubMed, Embase, Cochrane Library, and Web of Science. The data of objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS), and grade 3-4 adverse effects rate (grade 3-4 AEs%) were pooled for analyses. Cochrane risk of bias tool was applied for the quality judgment of randomized controlled studies (RCTs). RESULTS: Forty-one arms from 37 studies including 4,691 patients were included. Significant differences were presented in pooled ORR (22.9% versus 12.2%, OR =1.88, P<0.001) and DCR (62.7% versus 37.5%, OR =2.53, P<0.001) between CNA and MNA groups. The pooled median PFS was 3.66 months in CNA group versus 2.16 months in MNA group (WMD =1.50, P=0.028). No significant difference in pooled median OS was found between two groups (7.93 versus 7.50 months, WMD =0.43, P=0.449). 63.7% versus 25.4% of pooled grade 3-4 AEs% could be seen in CNA and MNA groups (OR =3.52, P<0.001). Additionally, the pooled results of PFS-6m and OS-6m in CNA group demonstrated significant advantages over MNA group (31.5% versus 28.7%, OR =1.31, P=0.049; 66.0% versus 56.7%, OR =1.34, P=0.029, respectively). In the subgroup analysis of CNA, use of ICIs, the positive expression of PD-L1 and ECOG-PS =0 were significantly associated with superior clinical outcomes (P<0.05). DISCUSSION: For advanced UC patients after first line agents, CNA had potential benefits than MNA in terms of ORR, DCR, median PFS, PFS-6m and OS-6m. However, CNA was associated with a significantly higher grade 3-4 AEs%. Furthermore, potential advantages were presented in CNA patients with ICIs usage, positive PD-L1 expression and ECOG-PS =0.

Coumarin and 3,4-dihydroquinolinone derivatives: Synthesis, antidepressant activity, and molecular docking studies.

BACKGROUND: Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. METHODS: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. RESULTS: Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. CONCLUSION: Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.

Synthesis and evaluation of anticonvulsant activities of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-b ]pyridine derivatives.

A series of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine derivatives containing triazole and other heterocycle substituents (methyltriazole, tetrazole, and triazolone) is described. Two experimental methods, maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, the neurotoxicity (NT) was tested using the Rotarod test. 5-(4-Chlorophenyl)-4,5-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6c) showed the best anticonvulsant activity. In the MES and PTZ experiments, the 50% effective dose (ED50 ) values of compound 6c were 9.5 and 20.5 mg/kg, respectively. From the therapeutic index (PI) values, 6c (MES and PTZ with PI values of 48.0 and 22.2, respectively) showed better safety than the clinical drugs carbamazepine (MES with PI value of 6.4) and ethosuximide (PTZ with PI value of 3.2). The biological activities of the compounds were verified by using molecular docking studies. Compound 6c showed significant interactions with residues at the benzodiazepine-binding site on gamma-aminobutyric acid A (GABAA ) receptors. The results of in vivo GABA estimation and bicuculline-induced seizures showed that 6c may have an effect on the GABA system. The physicochemical and pharmacokinetic properties of the target compounds were predicted.

Nuclear factor-kappa B activation inhibits proliferation and promotes apoptosis of vascular smooth muscle cells.

OBJECTIVES: To investigate the role of nuclear factor-kappa B (NF-κB) performed in cell proliferation and apoptosis of vascular smooth muscle cells (VSMCs), and to assess the mechanisms. METHODS: Human aorta VSMCs were divided into control, NF-κB inhibitor, NF-κB overexpression + NF-κB inhibitor, control vector + NF-κB inhibitor, NF-κB overexpression, and control vector groups. NF-κB overexpression vector was constructed and transfected into VSMCs. Proliferation of VSMCs in each group was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide. Apoptosis of VSMCs was detected by flow cytometry. The expression of NF-κB, FasL, and hypertension-related gene (HRG-1) was measured by Western blotting. RESULTS: NF-κB overexpression vector was constructed correctly by restriction endonuclease, and the results showed that the activation of NF-κB could inhibit the proliferation of VSMCs. The results of flow cytometry also confirmed that NF-κB overexpression promoted apoptosis of VSMCs. Mechanically, NF-κB overexpression could up-regulate the expression of FasL and HRG-1. CONCLUSIONS: NF-κB overexpression promotes apoptosis and inhibits cell proliferation of VSMCs. The mechanisms might be regulated by promoting FasL and HRG-1 expression.